CS272250B2 - Method of 4-/3,4-dichlorophenyl/-3,4-dihydro-1/2h/-naphthalenone production - Google Patents

Abstract

Prepn. of 4-(3,4-dichlorophenyl)-4-phenyl butanoic acid of formula (I) comprises: (a) selectively reducing 4-(3,4-dichlorophenyl)-4-ketobutanoic acid of formula (II) with a carbonyl cpd. in a polar protic or aprotic solvent at 0-100 deq.C to give 4-(3,4-dichlorophenyl) -4-hydroxybutanoic acid of formula (III); (b) converting (III) to 5-(3,4-dichlorophenyl) -dihydro-2(3H)furanone of formula (IV); and (c) reactinq (IV) with benzene, in an excess of benzene or in a reaction inert organic solvent in the presence of a Friedel-Craft catalyst at 0-100 deq.C. In the formulae Z = 3,4-dichlorophenyl. - (III) and its alkali metal or amine addn. salt and (IV) are new cpds.

Description

The present invention provides a novel useful process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone which serves as a key intermediate in the production of the antidepressant cis-CLS) (4S) -N-methyl. -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine, known as sertraline.

U.S. Pat. No. 4,536,518 to W. M. Welch et al., As well as W. M. Welch et al., Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984) discloses a process for preparing certain 4- (substituted-phenyl) -4- (optionally substituted phenyl) butanoic acids, wherein the optional substituent is always different from the alkoxy group. These particular 4,4-diphenylbutanoic acid derivatives are useful as intermediates leading to various antidepressant active cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine derivatives, including cis- (1S) (4S) -N-methyl -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalenamine (sertraline), which is particularly preferred from this class of substances. The prior art process described in W. M. Welche et al., Above, consists in the synthesis of the desired interoedial derivatives of 4,4-diphenylbutanoic acid in a series of steps starting from the corresponding benzophenone. For example, the appropriately substituted starting benzophenone is first subjected to base-catalyzed Stobbe condensation with diethyl succinate, followed by hydrolysis and decarboxylation of 48% aqueous hydrobromic acid to give the corresponding 4,4-diphenylbut-3-enoic acid, which is then reduced by catalytic hydrogenation or by the use of hydroiodic acid and red phosphorus. The desired x-intermediate 4,4-diphenylbutanoic acid is obtained as the final product.

Our co-pending Czechoslovak patent specification 272,238 describes an improved process for the preparation of 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid, which is known to be used as an intermediate for the production of 4- (3,4- dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone followed by sertraline. By the method of this related patent specification, the known starting material, 4- (3,4-dichlorophenyl) -4-ketobutanoic acid, is very easily converted through the novel intermediates 4- (3,4-dichlorophenyl) -4-hydroybutanoic acid. acid and 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone, na

4- (3,4-dichlorophenyl) -4-phenylbutanoic acid.

In parallel with the work on the above process, a new method for direct conversion of 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid and 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone to 4- (3) was found. The 4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone object of the present invention.

Accordingly, the invention provides a novel process for preparing 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone of Formula I

in which

R is a radical of formula III or IV

(III)

H

- c-ch ₉ choh

AND

The OH is reacted with benzene, optionally in the presence of an inert organic solvent, in the presence of a protic or Lewis acid catalyst at a temperature of from -20 ° C to 180 ° C until virtually complete alkylation of benzene with either the above hydroxy acid or the corresponding butyrolactone. followed by cyclization to the desired final product with a keto group in the ring.

Thus, the starting material used in the process of the present invention is either 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid or 5- (3,4-dichlorophenyl dihydro-2 (3H) -furanone). Preferred inert organic solvents for use in this process as cosolvents include halogenated lower aliphatic or aromatic hydrocarbons, with methylene chloride and o-dichlorobenzene being the most preferred solvents. The Lewis acids used as catalysts in this particular process include, but are not limited to, sulfuric acid, trifluoromethanesulfonic acid, hydrofluoric acid, methanesulfonic acid, polyphosphoric acid, phosphorus pentoxide, aluminum chloride, phosphorus pentachloride, titanium tetrachloride and various other. acidic exchangers, with the first four protic acids mentioned above being most preferred.

According to a preferred embodiment of this particular reaction, the molar ratio of the starting material of formula II to benzene and the acid catalyst is between about 1.0: 1.0 to 1.0: 20.0, respectively. from about 1.0: 0.1 to 1.0: 90.0, with the most preferred ratios of starting lactone to benzene and acid catalyst being in the range of about 1.0: 5.0: 0.1 to 1.0: 10.0: 90.0. In practice, the reaction is preferably carried out at a temperature ranging from about 15 ° C to 145 ° C, with the most preferred temperature range being about 15 ° C to 100 ° C. In the case where a protic acid such as sulfuric acid, trifluoromethanesulfonic acid or methanesulfonic acid, the preferred temperature range being from about 15 to 100 ° C, most preferably from about 20 to 100 ° C. When hydrofluoric acid is used as protic acid, the preferred temperature range is about 15 to 100 ° C, most preferably about 15 to 30 ° C.

Upon completion of this reaction step, the desired 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone is readily isolated from the reaction mixture in the manner customary for this type of reaction, ie by pouring the mixture under stirring with ice containing a mineral acid such as concentrated hydrochloric acid, mixing the resulting mixture, separating the phases and subsequently isolating the product from the organic phase, preferably by evaporating the solvent from the organic phase and subjecting the residue to crystallization, etc. This is a new one-step process. of the invention to prepare 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone from either 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone. or from 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid, terminated.

As mentioned above, the final product of the process of the invention, namely 4- (3,4-dichlorophenyl) -3,4-aihydro-1 (2H) -naphthalenone, is a valuable intermediate from which the anti-depressant cis- ( 1S) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine known as sertraline, as known in the art. Specifically, 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone is converted to racemically cis-N-methyl-4- (3,4-dichlorophenyl) -1, 2,3,4-tetrahydro-1-naphthalenamine and finally to the desired cis- (1S) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1- naphthalenamine in a multistep manner known from the prior art as described by WM Welch Jr., et al. U.S. Pat. No. 4,536,518 and Journal of Medicinal Chemistry, Vol. 27, δ. 11, p. 1508 (1984).

The starting hydroxy acid respectively. the lactone corresponding to formula II can be prepared as described in our above-cited related patent specification and in the preparations below.

The following Examples and Preparations illustrate the invention but are not intended to limit the scope of the invention in any way.

Example 1

Place in a 25 ml round-bottom flask equipped with a reflux condenser

8.0 g (0.083 mol) of methanesulfonic acid, which is heated to 95 DEG C. and a solution of 1.0 g of 0.004 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) is added dropwise over 20 minutes. -furanone (see Preparation 2) in 2 ml (0.022 mol) benzene. After completion of the dropwise addition, the reaction mixture was stirred at 95 ° C for 7 hours, then cooled and poured onto 60 g of ice. The aqueous mixture was warmed to room temperature (ca. 20 ° C) and extracted three times with 30 ml diethyl ether each time. The combined ether layers were combined, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated under reduced pressure to give an oily residue consisting of crude 4- (3,4-dichlorophenyl) -3 4-dihydro-1 (2H) -naphthalenone.

This material was chromatographed on 20 g of silica gel (70-230 mesh) using 25% ethyl acetate in hexane as eluent. 724 mg (62%) of pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone are obtained, which is identical in every respect to the product of Example 1 (E) of U.S. Pat. 4,536,518.

Example 2

To a reflux condenser, 20 ml, round-bottom reaction flask at room temperature (ca. 20 ° C) was added 1.0 g (0.004 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) - furanone (see Preparation 2), 4 ml (0.045 mol) benzene and 5 ml 96% sulfuric acid (0.094 mol). The resulting mixture was heated at 95 ° C for 1 hour and then at 140 ° C for 1.5 hours, then cooled to room temperature and poured onto 40 g of ice. The aqueous mixture was stirred at room temperature for 18 hours, the precipitated dark green solid was filtered off with suction and air-dried to constant weight. In this way it is obtained

740 mg (63%) of 4- (3,4-dichlorophenyl) -3,4-dihydro-l (2H) -naphthalenone of good quality rice kte1 1Ί by thin layer chromatography and by H NMR and C-NMR ^J spectroscopy contains only traces of 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid.

Example 3

To a 250 mL round bottom reaction flask equipped with a reflux condenser was charged at room temperature with 10 g (0.04 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone (see above). Preparation 2), 20 ml (0.22 mol) benzene and 80 g (0.830 mol) methanesulfonic acid. The reaction mixture was heated at 100 ° C for 20 hours, then cooled to room temperature and poured onto 200 g of ice. After addition of 50 ml of methylene chloride, the pH of the aqueous phase is adjusted to 11.3 by addition of 167 ml of 20% aqueous sodium hydroxide, an additional 50 ml of methylene chloride is added to the basified aqueous mixture and the aqueous phase is extracted. The separated aqueous layer is extracted with an additional 50 ml of methylene chloride, the combined organic extracts are dried over anhydrous magnesium sulfate, the drying agent is filtered off and the solvent is distilled off under atmospheric pressure. During the distillation, methylene chloride was replaced with a total of 50 ml of hexane and 75 ml of isopropyl ether. When the total volume of the distillation residue reaches about 90 ml, this solution is allowed to cool to room temperature (about 20 ° C) with stirring and stirred at this temperature for 18 hours. The precipitated pale yellow solid material was aspirated and air dried to constant weight. 7.24 g (62%) of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone of good quality are thus obtained.

Example 4

The procedure described in Example 1 was repeated except that polyphosphoric acid was used as the acid catalyst instead of methanesulfonic acid. Otherwise, the same molar proportions of the reactants were used as in Example 1. Again, pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone was obtained as the final product.

Similar results are obtained when phosphorus pentoxide, aluminum chloride or titanium tetrachloride is used as the acid catalyst instead of methanesulfonic acid, using the same molar proportions of the reactants as above.

Example 5

To 25 ml of the basic aqueous solution prepared as described in Preparation 1, containing 5.0 g (0.018 mol) of 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid, was added 25 ml of methylene chloride, and the pH of the aqueous phase was Adjust 5 ml of 96% sulfuric acid to 1,0. The layers were separated, the organic extract was transferred to a 100 mL round bottom flask equipped with a distillation apparatus, 25 mL (0.28 mol) of benzene was added thereto, and the methylene chloride was distilled off at atmospheric pressure.

A further 25 ml of 96% sulfuric acid (0.48 mol) and 5 ml (0.056 mol) of benzene were added to the distillation residue, the distillation apparatus was removed and the flask was equipped with a reflux condenser. The reaction mixture was heated at 95 ° C for 1 hour and then at 135 ° C for 3 hours, allowed to cool to room temperature (ca. 20 ° C) and poured onto 200 g of ice. The aqueous phase was extracted twice with methylene chloride (50 ml and 10 ml), the combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to give 2.89 g of a yellow foamy residue. According to thin layer chromatography and 1 H-NMR, spectroscopy is a major component of this material

4-C (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone.

Example 6

To a 125 ml polypropylene reaction flask was charged 3.0 g (0.012 mol)

Of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone (see Preparation 2) dissolved in 6 ml (0.067 mol of benzene) and 20 ml (1 ml) of this benzene solution is distilled at -78 ° C using a polypropylene tube. The reaction mixture was allowed to warm to room temperature (ca. 20 ° C) and stirred at this temperature for 18 hours, whereupon excess hydrofluoric acid and benzene were distilled off in vacuo, while hydrofluoric acid was removed. The system is purged with nitrogen, the reaction flask is disconnected from the hydrofluoric acid source, charged with 30 ml of methylene chloride and 5 ml of water, cooled to 0 ° C and the addition of ΟΪΓ, ΟΪΓ aqueous sodium hydroxide. The pH of the aqueous solution was adjusted to 12.0 (13 mL of base required), the organic layer was separated from the resulting two-phase system and the aqueous layer was back extracted with 30 mL of methylene chloride. The combined organic phases are dried over anhydrous magnesium sulphate, filtered, the organic filtrate is transferred to a 125 ml round-bottomed flask and concentrated by distillation at atmospheric pressure. After the volume has been reduced to about 30 ml, 40 ml of hexane are added and distillation is continued until the temperature of the distillate rises to 67 ° C. The heating bath was removed and the mixture was further stirred, whereupon a white precipitate began to precipitate within 5 minutes. The resulting white suspension was stirred for 16 hours to completely precipitate a white solid which was filtered off and dried to constant weight in a vacuum oven. This gives 3.43 g (9%) of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone of good quality, melting at 102-103 ° C. The pure product was further characterized by thin layer chromatography, 1 H-NMR spectroscopy and ¹³ C-NMR spectroscopy.

Example 7

To a 25 ml round bottom flask equipped with a reflux condenser was charged a solution of 3.0 g (0.012 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone (see Preparation 2) in 6 ml (0.067 mol) of benzene and 5.34 ml (0.060 mol) of trifluoromethanesulfonic acid were added to this solution with stirring at room temperature (ca. 20 ° C).

The mixture was stirred at room temperature for 5 minutes, then heated at 75 ° C for 1.5 hours, then allowed to cool to room temperature and poured onto 20 g of ice. After addition of ml of methylene chloride, the aqueous mixture was basified with 15 ml of 4N aqueous sodium hydroxide solution to pH 9.0, the layers were separated and the aqueous layer was extracted again with 30 ml of methylene chloride. Combine the organic layers, dry over anhydrous magnesium sulfate, filter the drying agent and transfer the filtrate to a 125 mL round bottom flask. The methylene chloride was distilled off at atmospheric pressure until the volume of the distillation residue in the flask was reduced to about 40 ml, then 40 ml of hexane was added and distillation continued until the temperature of the distillate reached 67 ° C. After removal of the heating bath, a white precipitate began to precipitate within 5 minutes. The resulting white suspension was stirred for 16 hours until the white solid precipitated, which was filtered off and dried to constant weight in a vacuum oven. 3.22 g (91%) of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone of good quality, melting at 103 DEG-104 DEG C., are thus obtained. The pure product was further characterized by thin vrst1 Ή VE H-NMR spectroscopy and ^J C-HMR spectroscopy.

Preparation 1

A mixture of 370.62 g (1.5 mol) of 4- (3,4-dichlorophenyl) -4-ketobutanoic acid / EA Steck et al., Journal of the American Chemical Society, Vol. 75 ₍ p. 1117 (1953)) and 1.505 liters of demineralized water are heated to 70 DEG-80 DEG C. with stirring and 130 ml of a 15N aqueous sodium hydroxide solution and 47.5 ml of a 1.5N aqueous solution are gradually added in aliquots. The total time required to dissolve completely is about 1 hour to give a dark brown solution having a pH of 10.73 at 78 ° C. This solution is transferred to a 5-liter flask and maintained at a temperature of about 65 ° C (± 3 ° C). A solution of 19.86 g (0.525 mol) of sodium borohydride in 100.3 ml of demineralized water containing 1.03 ml of a 15N aqueous solution of sodium hydroxide is added dropwise over 44 minutes. About 6 hours after the addition was complete, a sample was taken from the reaction mixture and analyzed by thin layer chromatography indicating complete absence of the starting keto acid. containing 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid as the sodium salt.

Preparation 2

To a warm aqueous basic solution containing 4- (3,4-dichlorophenyl) -4-hydroxybutyric acid as described in Preparation 1, 436 ml of 5 ₍ 8N hydrochloric acid) was added dropwise over 65 minutes with stirring and heating to 57-62 ° C. After the dropwise addition, the reaction mixture consisting of an oily and acidic aqueous layer is stirred vigorously under heating at 65-70 ° C for 4 hours, then allowed to cool to room temperature ( 20 ° C) At 1, 2, 2.5 and 3.5 hours after the start of the final heating, samples are taken from the mixture and analyzed by thin layer chromatography, which indicates that the conversion of the hydroxy acid to the lactone is complete in The mixture was allowed to cool gradually and then allowed to thaw for 16 hours at room temperature The precipitated white solid precipitate was filtered off with suction, washed twice in each case 80 ml of demineralized water, were first air dried on a suction funnel and then dried overnight (ca. 16 hours) in a vacuum oven at 46 ° C. 320 g (92%) of pure 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone are obtained, m.p. 64-65 ° C.

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone of formula 1 CD characterized in that the compound of formula II (II) wherein: R is a radical of formula III or IV (III) H AND -C-CH ₂ CH ₂ COOH (IV) AND OH is reacted with benzene, optionally in the presence of an inert organic solvent, preferably methylene chloride or O-dichlorobenzene, in the presence of a protic or Lewis acid catalyst at a temperature of from -20 ° C to 180 ° C, 2. The process according to claim 1, wherein the protic acid-acting catalyst is sulfuric acid, trifluoromethanesulfonic acid, hydrofluoric acid or methanesulfonic acid. 3. Process according to claim 1, characterized in that the starting material of the formula (II) is reacted with respect to benzene or benzene. acid catalyst used in a molar ratio of from 1.0: 1.0 to 1.0: 20.0, respectively. from 1.0: 0.1 to 1.0: 90.0. 4. The process of claim 1, wherein the reaction is carried out at a temperature of from 15 ° C to 145 ° C. 5. The process of claim 1 wherein the reaction is carried out in benzene in the absence of an inert organic solvent.